Abstract
Following ischemic stroke, polymorphonuclear neutrophils (PMNs) are rapidly recruited to the ischemic brain tissue and exacerbate stroke injury by release of reactive oxygen species (ROS), proteases and proinflammatory cytokines. PMNs may aggravate post-ischemic microvascular injury by obstruction of brain capillaries, contributing to reperfusion deficits in the stroke recovery phase. Thus, experimental studies which specifically depleted PMNs by delivery of anti-Ly6G antibodies or inhibited PMN brain entry, e.g., by CXC chemokine receptor 2 (CXCR2) or very late antigen-4 (VLA-4) blockade in the acute stroke phase consistently reduced neurological deficits and infarct volume. Although elevated PMN responses in peripheral blood are similarly predictive for large infarcts and poor stroke outcome in human stroke patients, randomized controlled clinical studies targeting PMN brain infiltration did not improve stroke outcome or even worsened outcome due to serious complications. More recent studies showed that PMNs have decisive roles in post-ischemic angiogenesis and brain remodeling, most likely by promoting extracellular matrix degradation, thereby amplifying recovery processes in the ischemic brain. In this minireview, recent findings regarding the roles of PMNs in ischemic brain injury and post-ischemic brain remodeling are summarized.
Highlights
Specialty section: This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology
Elevated polymorphonuclear neutrophils (PMNs) responses in peripheral blood are predictive for large infarcts and poor stroke outcome in human stroke patients, randomized controlled clinical studies targeting PMN brain infiltration did not improve stroke outcome or even worsened outcome due to serious complications
Transendothelial migration of PMN is mediated by adhesion molecules, e.g., of intercellular adhesion molecule 1 (ICAM-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1), which exhibit an increased expression after induction of experimental ischemic stroke [6, 7]
Summary
A possible mechanism, via which PMNs in peripheral blood aggravate secondary ischemic brain damage are PMN stalls resulting in microvascular occlusions even under conditions of successful arterial reopening [13,14,15]. The delivery of a humanized monoclonal antibody against CD11/ CD18 did not beneficially influence stroke outcome [20] These clinical findings necessitate a more differentiated assessment of the role of PMNs in the ischemic brain. PMNs release NETs, which are composed of PMN DNA, histones and granule components such as elastase and cathepsin G [21] These NETs have recently been reported to impair microvascular integrity after stroke induction in mice by electrocoagulation of the middle cerebral artery (MCA) [22]. PMNs are a heterogeneous group of leukocytes, which might obtain proinflammatory or anti-inflammatory properties depending on the tissue microenvironment [24] The former PMNs, which are widely referred to as N1 phenotype, contain high levels of proinflammatory cytokines, ROS, Fas (CD95) and ICAM-1 [24,25,26] (Table 1). MSC-derived EVs potently promote angiogenesis in the ischemic brain [33], when these EVs are obtained from MSCs
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